TMCO1-mediated Ca2+ leak underlies osteoblast functions via CaMKII signaling

Jianwei Li, Caizhi Liu, Yuheng Li, Qiaoxia Zheng, Youjia Xu, Beibei Liu, Weijia Sun, Yuan Li, Shuhui Ji, Mingwei Liu, Jing Zhang, Dingsheng Zhao, Ruikai Du, Zizhong Liu, Guohui Zhong, Cuiwei Sun, Yanqing Wang, Jinping Song, Shu Zhang, Jun Qin, Shukuan Ling (), Xianhua Wang () and Yingxian Li ()
Additional contact information
Jianwei Li: China Astronaut Research and Training Center
Caizhi Liu: China Astronaut Research and Training Center
Yuheng Li: China Astronaut Research and Training Center
Qiaoxia Zheng: Peking University
Youjia Xu: The Second Affiliated Hospital of Soochow University
Beibei Liu: Peking University
Weijia Sun: China Astronaut Research and Training Center
Yuan Li: The Second Affiliated Hospital of Soochow University
Shuhui Ji: Beijing Proteome Research Center, Beijing Institute of Radiation Medicine
Mingwei Liu: Beijing Proteome Research Center, Beijing Institute of Radiation Medicine
Jing Zhang: Tsinghua University
Dingsheng Zhao: China Astronaut Research and Training Center
Ruikai Du: China Astronaut Research and Training Center
Zizhong Liu: China Astronaut Research and Training Center
Guohui Zhong: China Astronaut Research and Training Center
Cuiwei Sun: Peking University
Yanqing Wang: China Astronaut Research and Training Center
Jinping Song: China Astronaut Research and Training Center
Shu Zhang: The Fourth Military Medical University
Jun Qin: Beijing Proteome Research Center, Beijing Institute of Radiation Medicine
Shukuan Ling: China Astronaut Research and Training Center
Xianhua Wang: Peking University
Yingxian Li: China Astronaut Research and Training Center

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Transmembrane and coiled-coil domains 1 (TMCO1) is a recently identified Ca2+ leak channel in the endoplasmic reticulum. TMCO1 dysfunction in humans is associated with dysmorphism, mental retardation, glaucoma and the occurrence of cancer. Here we show an essential role of TMCO1 in osteogenesis mediated by local Ca2+/CaMKII signaling in osteoblasts. TMCO1 levels were significantly decreased in bone from both osteoporosis patients and bone-loss mouse models. Tmco1−/− mice exhibited loss of bone mass and altered microarchitecture characteristic of osteoporosis. In the absence of TMCO1, decreased HDAC4 phosphorylation resulted in nuclear enrichment of HADC4, which leads to deacetylation and degradation of RUNX2, the master regulator of osteogenesis. We further demonstrate that TMCO1-mediated Ca2+ leak provides local Ca2+ signals to activate the CaMKII-HDAC4-RUNX2 signaling axis. The establishment of TMCO1 as a pivotal player in osteogenesis uncovers a novel potential therapeutic target for ameliorating osteoporosis.

Date: 2019
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DOI: 10.1038/s41467-019-09653-5

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